title: Neonatal E. coli infection causes neuro-behavioral deficits associated with hypomyelination and neuronal sequestration of iron.
abstract: Recent evidence indicates that inflammatory insults in neonates significantly influenced white matter development and caused behavioral deficits that manifest in young adulthood. The mechanisms underlying these developmental and behavioral complications, however, are not well understood. We hypothesize that acute brain inflammation caused by neonatal infection reduces the bioavailability of iron required for oligodendrocyte maturation and white matter development. Here, we confirm that peripheral Escherichia coli infection in neonates at postnatal day 3 (P3) caused acute brain inflammation that was resolved within 72 h. Nonetheless, transient early life infection (ELI) profoundly influenced behavior, white matter development, and iron homeostasis in the brain. For instance, mice exposed to E. coli as neonates had increased locomotor activity and impaired motor coordination as juveniles (P35) and young adults (P60). In addition, these behavioral deficits were associated with marked hypomyelination and a reduction of oligodendrocytes in subcortical white matter and motor cortex. Moreover, ELI altered transcripts related to cellular sequestration of iron in the brain including hepcidin, ferroportin, and L-ferritin. For example, ELI increased hepcidin mRNA and decreased ferroportin mRNA and protein in the brain at P4, which preceded increased L-ferritin mRNA at P12. Consistent with the mRNA results, L-ferritin protein was robustly increased at P12 specifically in neurons of E. coli infected mice. We interpret these data to indicate that neonatal infection causes significant neuronal sequestration of iron at a time point before myelination. Together, these data indicate a possible role for aberrant neuronal iron storage in neonatal infection-induced disturbances in myelination and behavior.
authors.affiliation: Department of Neuroscience, Division of Oral Biology, Institute for Behavioral Medicine Research, and Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio 43210, Abbott Nutrition, Columbus, Ohio 43219, and Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27708.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Lieblein-Boff
authors.forename: Daniel B
authors.initials: DB
authors.lastname: McKim
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Shea
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Zhen
authors.initials: Z
authors.lastname: Deng
authors.forename: Caroline
authors.initials: C
authors.lastname: Sawicki
authors.forename: Ning
authors.initials: N
authors.lastname: Quan
authors.forename: Staci D
authors.initials: SD
authors.lastname: Bilbo
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bailey
authors.forename: Dana M
authors.initials: DM
authors.lastname: McTigue
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Godbout
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004927:Escherichia coli Infections / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000502:physiology; D019957:Motor Skills Disorders / Q000209:etiology; D009186:Myelin Sheath / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007501:Iron